Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, Karnataka, India.
Metallomics. 2010 Nov;2(11):754-65. doi: 10.1039/c0mt00028k. Epub 2010 Oct 21.
Ternary cobalt(III) complexes [CoL(B)] (1-3) of a trianionic tetradentate phenolate-based ligand (L) and phenanthroline bases (B), viz. 1,10-phenanthroline (phen in 1), dipyridoquinoxaline (dpq in 2) and dipyridophenazine (dppz in 3) are synthesized, characterized from X-ray crystallographic, analytical and spectral techniques, and their utility in photodynamic therapy (PDT) of thyroid diseases caused by TSH receptor dysfunction is probed. The complexes display a visible spectral band within the PDT spectral window at ~690 nm. Photodynamic potential was estimated through DNA cleavage activity of the dpq and dppz complexes in UV-A light of 365 nm and red light of 676 nm. The reactions proceed via the hydroxyl radical pathway. The complexes retain their DNA photocleavage activity in red light under anaerobic conditions, a situation normally prevails in hypoxic tumor core. Investigation into the photocytotoxic potential of these complexes showed that the dppz complex 3 is approximately 4-fold more active in the HEK293 cells expressing human thyrotropin receptor (HEK293-hTSHR) than in the parental cell line and has an insignificant effect on an unrelated human cervical carcinoma cell line (HeLa). Photoexcitation of complex 3 in HEK293-hTSHR cells leads to damage hTSHR as evidenced from the decrease in cAMP formation both in absence and presence of hTSH and decrease in the TSHR immunofluorescence with a concomitant cytoplasmic translocation of the membrane protein, cadherin. The involvement of hTSHR is evidenced from the ability of complex 3 to bind to the extracellular domain of hTSHR (hTSHR-ECD) with a K(d) value of 81 nM and from the photocleavage of hTSHR-ECD.
合成了三元钴(III)配合物[CoL(B)]（1-3），其中 L 为阴离子四齿酚基配体，B 为邻菲咯啉碱基（phen 在 1 中）、二吡啶并喹喔啉（dpq 在 2 中）和二吡啶并吩嗪（dppz 在 3 中）。通过 X 射线晶体学、分析和光谱技术对其进行了表征，并探讨了它们在 TSH 受体功能障碍引起的甲状腺疾病的光动力疗法（PDT）中的应用。这些配合物在 ~690nm 的 PDT 光谱窗口内显示出可见光谱带。通过 dpq 和 dppz 配合物在 365nm 的紫外-A 光和 676nm 的红光中的 DNA 断裂活性来估计光动力潜力。反应通过羟基自由基途径进行。在缺氧肿瘤核心中通常存在的厌氧条件下，这些配合物在红光下保持其 DNA 光裂活性。对这些配合物的光细胞毒性潜力的研究表明，dppz 配合物 3 在表达人促甲状腺激素受体（HEK293-hTSHR）的 HEK293 细胞中的活性比在亲本细胞系中高约 4 倍，并且对无关的人宫颈癌细胞系（HeLa）没有显著影响。在 HEK293-hTSHR 细胞中，配合物 3 的光激发导致 hTSHR 受损，这从 cAMP 形成的减少（无论是在缺乏 hTSH 还是存在 hTSH 的情况下）以及 TSHR 免疫荧光的减少得到证明，同时膜蛋白钙粘蛋白发生细胞质易位。配合物 3 能够与 hTSHR 的细胞外结构域（hTSHR-ECD）结合，其 K(d)值为 81 nM，并且能够光裂 hTSHR-ECD，这证明了 hTSHR 的参与。
